Researchers have shown for the first time that malfunctioning mitochondria, the cell’s energy generators, may directly cause cognitive decline in neurodegenerative diseases.
By creating a new tool that temporarily boosts mitochondrial activity in the brain, scientists restored memory performance in mouse models of dementia.
The discovery hints that energy failure inside neurons could happen before brain cells die, potentially offering a new target for future Alzheimer’s treatments.
In a study published in Nature Neuroscience, researchers from Inserm and the University of Bordeaux at the NeuroCentre Magendie, working with scientists at the Universite de Moncton in Canada, reported a major step forward in understanding dementia.
Their results showed a direct cause-and-effect link between faulty mitochondrial activity and cognitive symptoms associated with neurodegenerative disease.
Brain energy and memory loss
The team created a highly specific tool that allowed them to temporarily increase mitochondrial activity in animal models of neurodegenerative disease. When they boosted the brain’s energy machinery, memory problems improved.
Although the findings are still early and were observed in animal models, they point to an intriguing possibility: mitochondria may not simply break down after brain disease begins. Instead, their failure may help drive the symptoms that appear as dementia develops.
That idea could reshape how scientists think about future treatments. If brain cell energy failure contributes to memory loss, then restoring mitochondrial function may one day become a strategy for slowing or reducing symptoms.
Why mitochondria matter in the brain
A mitochondrion is a small structure inside the cell that helps generate the energy required for normal function. This matters especially in the brain, which consumes a large amount of the body’s energy.
Neurons depend on that energy to send signals to one another. When mitochondrial activity drops, neurons may no longer have enough power to work properly. Over time, that energy shortage could weaken communication in the brain and contribute to memory and thinking problems.
Neurodegenerative diseases involve the gradual decline of neuronal function, followed by the death of brain cells. In Alzheimer’s disease, researchers have long observed that mitochondrial problems appear alongside neuronal degeneration, often before cells die.
Until recently, however, it was difficult to determine whether mitochondrial dysfunction helped cause the disease process or merely appeared as a result of it.
A tool designed to recharge mitochondria
To explore that question, the researchers developed a tool that can temporarily stimulate mitochondrial activity. Their reasoning was simple but powerful. If increasing mitochondrial activity improved symptoms in animals, that would suggest mitochondrial impairment can come before neuron loss and contribute directly to cognitive decline.
Earlier work by the research teams had already identified a role for G proteins, which have the specific role of enabling the transfer of information within cells, in regulating mitochondrial activity in the brain.
In the 2025 study, they built an artificial receptor called mitoDreadd-Gs. This receptor was designed to activate G proteins directly inside mitochondria, which in turn stimulated mitochondrial activity.
When mitoDreadd-Gs was activated in the brain, mitochondrial activity returned to normal levels. Memory performance also improved in mouse models of dementia.
A possible new target for Dementia Research
“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases, suggesting that impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration,” explains Giovanni Marsicano, Inserm research director and co-senior author of the study. (ANI)
